Fighting renal cell carcinoma with natural compounds backed by science

Renal cell carcinoma (RCC), is a kidney cancer that originates in the lining of the proximal convoluted tubule (a part of the very small tubes in the kidney that transport primary urine), and is the most common type of kidney cancer in adults responsible for approximately 90–95% of cases.

Over the last decades, an increased number of the signalling pathways and mechanisms involved in the progression of this cancer have been studied, as a consequence significant advances in the treatment of RCC have been reported using FDA approved drugs (such as inhibitors of mTOR like everolimus and temsirolimus, and the tyrosine kinase inhibitors/TKIs like sorafenib, sunitinib, pazopanib and axitinib), that demonstrated clinical benefit and increased survival in patients with metastatic disease.

However, sometimes the patients eventually develop resistance to these drugs, accordingly new and more effective therapies and preventative strategies are needed.

One of these strategies is by using natural products that lack the severe side effects common to synthetic compounds.

This review,

"The Role of Compounds Derived from Natural Supplement as Anticancer Agents in Renal Cell Carcinoma: A Review",

published in 2018 (by Inamul Haque, Arvind Subramanian, Chao H. Huang, Andrew K. Godwin, Peter J. Van Veldhuizen, Snigdha Banerjee and Sushanta K. Banerjee from the University of Kansas) provides valuable information for possible use of several natural products alone or in combination with chemotherapy for the prevention and treatment of RCC (please always check the literature of the original studies in the review).

These natural products are:

Epigallocatechin-3-Gallate

Epigallocatechin-3-gallate (EGCG), is an active and major constituent of green tea (Camellia sinensis), and several studies have showed so far that it has anti-tumour properties in RCC, since it inhibits tumour growth and invasiveness by up-regulating the expression of a protein called TFPI-2 (through inhibition of DNA methyl-transferase/DNMT activity). 

This TFPI-2 or tissue factor pathway inhibitor-2 protein, is inversely correlated to the aggressiveness of the tumour cells. Therefore, higher concentrations of TFPI-2 would decrease the malignancy of these cells and most likely induce apoptosis. 

Moreover, several studies reviewed by the authors indicated that

• EGCG may play a preventive role in the development of RCC (alone or in combination),

• EGCG induces apoptosis, inhibiting the proliferation and migratory potential of RCC cell lines,

• EGCG was proven an extremely viable RCC treatment in vitro by independent and multiple experiments, and

• an extensive epidemiological study reported an inverse correlation between green tea consumption and overall RCC tumour burden.

Though EGCG is predominantly found in green tea (250 ml of brewed green tea typically contains about 50–100 mg of EGCG), it also exists in small amounts in (source HealthLine.Com):

• Tea: white, oolong, and black teas
• Fruits: cranberries, strawberries, blackberries, kiwis, cherries, pears, peaches, apples and avocados
• Nuts: pecans, pistachios and hazelnuts.

Overall, according to the studies considered, EGCG can be used both as preventative and as therapeutic approach for RCC.

Source Via Vocal: "Green tea extract EGCG an effective chemopreventive polyphenol"

Englerin A

Englerin A, a natural product derived from the root and stem bark of the African plant Phyllanthus engleri, was also identified to preferentially inhibit the cell growth and viability of RCC through a drug screen.

Probably, the growth of RCC cell lines is inhibited by Englerin A through necrotic cell death rather than apoptosis. But although a study indicated that apoptotic bodies were not present after Englerin A treatment, another study indicated otherwise since apoptosis and autophagy were noticed after 24 h of treatment. In addition, a study also suggested that Englerin A-induced inhibition of RCC growth, due to cell cycle arrest.

In another study, it was demonstrated that Englerin A inhibits molecular changes associated with the epithelial-mesenchymal transition (EMT), considered the hallmark of all metastasis in malignancies including renal cancer, by up-regulating the epithelial markers and down-regulating the mesenchymal/stem cell markers. Meaning, Englerin A inhibits RCC metastasis.

In the same study, they also found that Englerin A inhibits TGF-β1-induced angiogenesis.

Several other studies demonstrated that Englerin A alters lipid metabolism, induces endoplasmic reticulum stress, and in turn generates an excess of ceramides, which are lethal to RCC cells. Furthermore, Englerin A induces an acute inflammatory response.

However, the in vivo models conducted so far on mice indicated that the levels of Englerin A required for anti-tumour activity may be lethal.

Quercetin

Quercetin, a flavonoid found in many food items such as tea, onions, grapes and apples has been shown to exhibit a chemopreventive role in several cancers including liver, lung, prostate cancers, breast and renal cancer.

In particular, quercetin was very effective when used in combination with hyperoside (the 3-O-galactoside of quercetin) in renal cancer cells, by down-regulating miRNA-27a (A Novel Biomarker and Potential Therapeutic Target in Tumours).

The microRNAs (miRNAs) are endogenous, conserved and small non-coding RNA molecules that regulate gene expression at the post-transcriptional level, and it has been reported that miR-27a might play a vital role in tumour development. Moreover, miR-27a could also be an oncogene or a tumour suppressor in several types of cancer, including colon cancer, pancreatic cancer, breast cancer, bladder cancer and hepato-cellular carcinoma.

So, the reduction of miRNA-27a after quercetin treatment, combined with an increase in the zinc finger and BTB domain-containing protein 10, triggers in the end a decrease in specificity protein (SP) transcription factors.

These transcription factors are highly expressed in cancer cells, and their reduction shows the therapeutic potential of quercetin.

Quercetin has been reported also to increase the activity of EGCG in terms of bioavailability in animal models by inhibiting COMT (catechol-O-methyltransferase) activity.

This is very important, since methylation by COMT can significantly decrease the chemopreventive activity of EGCG in several cancers.

In particular, COMT catalyses the methylation of various endo-biotic and xenobiotic substances, and protects DNA from oxidative damage. When the association between a common functional polymorphism of COMT Val158Met and DNA methylation status in the stomach was investigated, the conclusion was that the COMT polymorphism may influence the susceptibility to gene methylation in the gastric mucosa.

Let's see now the role of quercetin in EMT, considered the hallmark of all migration and metastasis in malignancies.

A transcription factor that plays a key role in EMT is Snail, a zinc-finger transcription factor, that when is silenced inhibits cellular proliferation, cell cycle progression, cancer cell migration and promotes apoptosis in cell lines.

Surprisingly, quercetin together with snail silencing provides even strong suppressive effects toward these cells.

Finally, isoquercetin (hydrolysed in vivo to quercetin) is currently being assessed in combination with sunitinib (clinicaltrials.gov: NCT02446795) to understand if isoquercetin is able to reduce sunitinib-induced fatigue which is being reported in 51–63% of advanced RCC patients.

It is estimated that the average person consumes 10–100 mg of quercetin daily, through various food sources (HealthLine.Com).

Overall, according to these studies, quercetin has significant therapeutic potential.

Coumarin

Coumarin, a compound found in different parts of plants and having the highest concentration in fruits, followed by roots, seeds and leaves (Dipteryx odorata, Anthoxanthum odoratum, Galium odoratum, Hierochloe odorata, sweet-clover, Cinnamomum cassia, Carphephorus odoratissimus, Justicia pectoralis, mullein, and in many cherry blossom tree varieties of the genus Prunus, and finally in strawberries, black currants, apricots, and cherries), has diverse pharmacological and biological properties such:

• as anti-thrombotic,
• scavenging of reactive oxygen species,
• anti-mutagenic,
• anti-bacterial,
• cycloxygenase inhibition,
• as well as an anti-tumorigenic effect.

Moreover, multiple studies so far have demonstrated that coumarins possess cytostatic and cytotoxic properties, inhibiting growth in several human cancer cell lines in vitro.

In particular, some clinical trials, have shown anti-proliferative activities against RCC:

• Coumarin plus cimetidine: Yet another angle for therapy of renal cell carcinoma. J. Clin. Oncol. 1987, 5, 836–837.
• Treatment of metastatic renal cell carcinoma with coumarin (1,2-benzopyrone) and cimetidine: A pilot study. J. Clin. Oncol. 1987, 5, 862–866.

• Coumarins as anticancer agents: A review on synthetic strategies, mechanism of action and SAR studies. Eur. J. Med. Chem. 2015, 101, 476–495.

Moreover, a derivative of coumarin (consisting of 1,2,4-triazolin-3-one attached to 4-methylcoumarin) was found also to have encouraging activity against RCC cell lines. While, a recent derivative named coufin, showed in a 2014 study potent anticancer activity both in 2D (monolayer culture) and 3D (tumour spheroid culture) by inhibiting microtubule formation and blocking the cell cycle.

In conclusion, since coumarin has low toxicity, there is a scientific rationale for using coumarin with other compounds in an attempt to increase their efficacies.

Curcumin

Curcumin, a natural polyphenolic phytochemical isolated from dried rhizomes of turmeric plant (Curcuma longa) and used for centuries, has shown to have numerous pharmacological activities, including:

• anti-inflammatory,
• antiviral,
• anti-oxidant,
• wound healing,
• hepatoprotective,
• and anti-microbial effects.

Moreover, curcumin has been used as a chemopreventive agent and as an anti-cancer therapy in several human carcinomas, including colorectal, melanoma, lymphoma, breast, thyroid, head and neck, prostate, pancreatic, ovarian and RCC.

Even though, curcumin has been reported to efficiently induce apoptosis in vitro in cancer cell lines the mechanism remains poorly understood.

Moreover, curcumin has been proven to increase the efficacy of chemotherapeutic drugs. For example, a study reported that combined treatment with curcumin and temsirolimus in RCC cell lines, induces apoptosis.

Most of the studies using turmeric extracts (that contain mostly curcumin) have dosages usually exceeding 1 gram per day. However, it would be very difficult to reach these levels just by using turmeric as a spice in your food, since curcumin is poorly absorbed into our bloodstream. So, in order to increase its bioavailability we should consume it with black pepper, which contains piperine, a natural substance that enhances the absorption of curcumin by 2,000% (HealthLine.Com).

To conclude, although curcumin has been so far successfully proven to be very effective in vitro, it exhibits lesser effects in vivo due to poor bioavailability, poor absorption, rapid metabolism in liver cells and intestinal wall.

Resveratrol

Resveratrol, a naturally occurring polyphenolic compound found in grapes and at least 72 medicinal and edible plants species such as Polygonum cuspidatum, Veratrum grandiflorum, Arachis hypogaea (peanut), Rhizoma polygoni cuspidate, Yucca Schidigera, Cassia quinquangulata, Rheum rhamponticum among others (source), has been reported to induce apoptosis, inhibit tumour growth, suppress angiogenesis (Source Via Vocal: "Fighting angiogenesis with natural compounds backed by science") and metastasis in various malignancies including RCC.

It has been indicated that resveratrol significantly inhibits the RRC cell proliferation and exerts an antitumor effect by concomitant inhibition of the expression of the Vascular endothelial growth factor (VEGF), a potent angiogenic factor produced by many cells that stimulates the formation of blood vessels, a vital feature of the RCC microenvironment.

Another study demonstrated the pro-apoptotic and anti-invasive role of resveratrol in RCC, and these results suggest that it suppresses the activation of Signal Transducers and Activators of Transcription 3/5 (STAT3/5) proteins, which are aberrantly activated in RCC and have been linked to many human cancers.

Furthermore, it was documented that resveratrol can induce S-phase arrest and apoptosis, decrease mitochondrial membrane potential and suppress colony formation in RCC.

Moreover, treatment with resveratrol in combination with sorafenib increases sorafenib's induced inhibitory effect on phosphorylation of STAT3/5 protein and in turn results in down-regulation of various oncogenic gene products.

In addition to its anti-tumour action, resveratrol can exhibit anti-tumour immune response in mice by efficiently suppressing regulatory T cells, inhibiting TGF-β level and increasing IFN-γ expressing CD8+ T cells.

Taken together, resveratrol may, therefore, be an effective anti-tumour therapy drug and improve outcomes for RCC patients.

Other Natural Products

Honokiol, is a biologically active biphenolic compound isolated from Magnolia spp. bark, that has shown to exhibit an anticancer effect.

For example, it was demonstrated that honokiol inhibits metastasis through reversing EMT and suppressing cancer stem cell properties via modulating miR-141/ZEB2 axis (miR-200 family members such as miR-141, miR-200a, miR-200b, miR-200c, miR-429 are expressed in epithelial cells and help maintain an epithelial phenotype namely inhibiting metastasis).

Genistein is one of the principal isoflavones found in soybeans that inhibits several cancers by modulating different signalling pathways involved in cell cycle progression, apoptosis, invasion, angiogenesis and metastasis.

For example, genistein inhibits angiogenesis in vivo by down-regulating the expression of VEGF and basic fibroblast growth factor (bFGF), the two crucial players in angiogenesis in RCC.

Sulforaphane (SFN) is an isothiocyanate derived from cruciferous vegetables such as broccoli (Brassica oleracea) and has been shown to act as a protectant in normal kidney tubular cells against nephrotoxicants secreted by these cells, and also to exhibit a pro-apoptotic effect on cancer cells by stimulating mitochondrial metabolism.

For example, studies found that SFN delays the resistance caused by chronic use of everolimus monotherapy and increases the efficacy of everolimus in RCC cell lines.

Amygdalin is a cyanogenic substance found in apricots, peaches, apple, cherry, plums and other rosaceous fruit seeds, and recently it has been reported that amygdalin inhibits the growth of RCC cells by blocking adhesion and migration via an integrin-dependent mechanism.

Thymoquinone is a monoterpene natural polyphenolic compound found in the seed oil of black cumin (Nigella sativa L.) seeds and known to have anti-cancer properties.

Thymoquinone has recently been reported for its role in inducing apoptosis in renal carcinoma cells.

Kahweol, a diterpene molecule from coffee beans, has been reported to enhance the sensitivity to sorafenib in renal cell carcinoma cells.

Alpinumisoflavone, is isolated from Erythrina lysistemon, and the mechanism of its anti-cancer effect was recently uncovered, suggesting that suppresses the tumour growth and metastasis through modulating miR-101/RLIP76 signalling (MiR-101: a potential therapeutic target of cancers).

16-hydroxycleroda-3,13-dien-15,16-olide, a clerodane diterpene (CD), isolated from Polyalthia longifolia var. pendula leaves, has been also shown to inhibit the proliferation of various human cancer cell lines.

In particular, a recent study studied the mechanism of action of CD against RCC, and suggested that it inhibits the cell proliferation and induces mitochondrial-dependent apoptosis.

Finally, a very recent report demonstrated that Korean red ginseng extract can enhance the anticancer effect of sorafenib in RCC.

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